Biomaterials involving resorbable or degradable, macroporous bioactive glass material, which can be used either for the restoration of hard tissues or as the tissue engineering scaffold, as well as preparation methods for such materials is described herein. Also, bone graft compositions that include a bioactive glass scaffold and are characterized in that the bioactive glass scaffold has a high compressive strength, is osteoconductive and osteostimulative and resorbs at a rate consistent with the formation of new bone, are described. Also, methods of using the bone graft compositions for regeneration of hard tissues, especially for joint reconstruction (such as in, e.g., developmental dysplasia (dislocation) of the hip or DDH, and tibial plateau elevation), cranial reconstruction and spine fusion, are provided.
Autogenous bone grafts are often the gold standard for regeneration of hard tissues in adults as well as children. The drawbacks, however, are the harvest time, donor site morbidity, graft resorption, modeling changes, and harvest volume limitations. The clinician has to choose the site of bone harvest wisely, taking into account the nature of the reconstruction and volume requirements.
Also, due to the limited quantity of autogenous bone, especially in children, an additional bone graft is needed to satisfactorily reconstruct hard tissue. Allografts have been used for this purpose. However, the use of allografts may result in problems, such as an increased risk of disease transmission along with possible graft rejection that could result in delayed healing and biomechanical failure of the reconstructed bone.
Also, currently available synthetic bone grafts and bone cements are incapable of providing the mechanical strength necessary while being resorbed by the body and replaced with new bone. More specifically, putties and particulate graft materials have often insufficient strength and do not maintain their position in the surgical site. Methacrylates are not resorbable and replaced with new bone while calcium phosphates and calcium phosphate cements have an insufficient resorption profile or are too weak for use in certain hard tissue repairs, such as in hip reconstruction.
Clinically, the ideal graft material for hard tissue reconstruction should be (1) highly bioactive, (2) should stimulate the activity of bone forming cells, (3) should possess sufficient mechanical strength to support the filled space, (4) function as an osteoconductive scaffold to promote new bone growth to accelerate healing of the defect, and (5) should be resorbed at a rate consistent with the formation of new bone to assure the success of the reconstruction.
“Bioactive glass” or “bioglass,” for example, 45S5, contains 45% silica, 24.5% calcium oxide, 24.5% sodium oxide and 6% phosphate by weight is highly bioactive possessing the fastest biological response when implanted in living tissue among all of the bioactive glass compositions. Since the first report by Hench et al. (L. L. Hench, R. J. Splinter, T. K. Greelee, and W. C. Allen, “Bonding Mechanisms at the Interface of Ceramic Prosthetic Materials”, J. Biomed. Mater. Res., No. 2, 117-141, 1971) that Bioglass compositions could bond with bone chemically, bioactive glass has been considered a material that demonstrates a fast biological response (greater bioactivity) than any other material.
Also, such glass material has been used for restoration of bone defects in clinical practice for over ten years, and such clinical applications have proven successful in that this glass can bring along not only the benefit of osteoconduction, but also the bioactivity to stimulate the growth of bone tissues. Many recent studies have revealed that the degradation products of bioactive glass can enhance the generation of growth factors, facilitate cellular proliferation and activate gene expression of osteoblasts. Moreover, bioactive glass is the only synthetic biomaterial so far that can both bond with bone tissues and soft tissues. These unique features of this glass have created a great potential for its clinical application as a type of medical device, and thereby, attracted great attention from both academia and the industrial sector. Despite its excellent biocompatibility and bioactivity, bioactive glass can be now produced only in a granular form for clinical application. For restoration of bone defects, macroporous and block scaffold materials with a particular mechanical strength are often needed to fill in and restore such defects. Even in the field of tissue engineering, which receives worldwide attention and evolves rapidly, macroporous bioactive scaffold materials are similarly demanded to serve as cell carriers.
As a result, bioglass products have been cleared by the U.S. Food and Drug Administration (FDA) as osteostimulative. The stimulation of osteoblast proliferation and differentiation has been evidenced during in vitro osteoblast cell culture studies by increased DNA content and elevated osteocalcin and alkaline phosphatase levels. Bioglass with osteostimulative properties can enhance the production of growth factors, promote the proliferation and differentiation of bone cells (I. D. Xynos, A. J. Edgar, and L. D. K. Buttery et al, “Ionic Products of Bioactive Glass Dissolution Increase Proliferation of Human Osteoblasts and Induce Insulin-like Growth Factor II mRNA Expression and Protein Synthesis,” Biochem. and Biophysi. Res. Comm. 276, 461-65, 2000; I. D. Xynos, A. J. Edgar, and L. D. K. Buttery et al, “Gene-Expression Profiling of Human Osteoblasts Following Treatment with the Ionic Products of Bioglass® 45S5 Dissolution,” J. Biomed. Mater. Res., 55, 151-57, 2000; and I. D. Xynos, M. V. J. Hukkanen, J. J. Batten et al, “Bioglass® 45S5 Stimulates Osteoblast Turnover and Enhance Bone Formation In Vitro: Implications and Applications for Bone Tissue Engineering,” Calcif. Tissue Int., 67, 321-29, 2000), and stimulate new bone formation with new bone observed simultaneously at the edge and center of the defect area.
U.S. Pat. No. 7,705,803 to Chang et al. discusses a resorbable, macroporous bioactive glass scaffold produced by mixing with pore forming agents and specified heat treatments. The '803 patent also describes the method of manufacture for the porous blocks. The compressive strength of the bioglass scaffold described by Chang et al. is 1-16 MPa.
As such, bioglass-based graft materials for hard tissue reconstructions, including in DDH and other related bone conditions, having a relatively high compressive strength especially for use in application that require high load bearing implant materials may be desirable. Also, the known procedures could benefit from advancements in techniques, instrumentation, and materials to make the results more reproducible and reliable.
Research studies in the past have suggested that besides the composition of the material, its structure can directly influence its clinical applications as well. The macroporous and block scaffold materials with bioactivity whose pore sizes are in the range of 50-500 microns are most suitable to be used as materials either for the restoration of bone defects, or as cell scaffolds. Any macroporous biomaterial having a pore size within the said range can bring benefits to the housing and migration of cells or tissue in-growth, as well as to the bonding of such a material to living tissues, thereby achieving the goals of repairing defects in human tissues and reconstructing such tissues more effectively.
Moreover, the subject of the biomaterials that are both resorbable and macroporous has now become an integral part of tissue engineering studies that have been rapidly developed in recent years, where scaffolds made of such macroporous materials can be adopted to serve as cell carriers so that cells can grow in the matrix materials and constitute the living tissues that contain genetic information of the cell bodies, and such tissues can be in turn, implanted into human bodies to restore tissues and organs with defects. Therefore, resorbable, macroporous bioactive glass scaffold materials possess wide-ranging potential for their applications as cell scaffolds either for restoration of defects in hard tissues, or for the purpose of in vitro culture of bone tissues.
U.S. Pat. Nos. 5,676,720 and 5,811,302 to Ducheyne, et al, teach a hot-pressing approach using inorganic salts such as calcium carbonate and sodium bicarbonate as the pore-forming agents to prepare and manufacture macroporous bioactive glass scaffolds which have the compositions of CaO—SiO2—Na2O—P2O5, and which are designed to function as the cell scaffolds used for in vitro culture of bone tissues. Nevertheless, this hot-pressing approach if adopted would entail high production costs, and furthermore, controlling the composition of the finished products is difficult because the composition will be affected by the remnants that result after sintering the inorganic salts used as pore-forming agents. Additionally, Yuan, et al. have adopted oxydol as a foaming agent to prepare and manufacture 45S5 bioactive glass scaffolds under a temperature of 1000° C., with the scaffolds produced in this way being bioactivity and having the ability to bond together with bone tissues Q. Biomed. Mater. Res; 58:270-267, 2001). But according to our testing results, the glasses will become substantially crystallized and their resorbability/degradability will decrease if they are sintered under a temperature of 1000° C. In addition, it is quite difficult to control the pore size and pore number of the materials when oxydol is used as the foaming agent.
Mechanical strength is also an important factor for performance of macroporous bioactive glass scaffold materials, and relevant studies have suggested that any compressive strength below 1 MPa would result in the poor applicability of these scaffold materials, and thus, in the course of applying them either as cell scaffolds or for the purpose of restoration of bone injuries, such materials would be very prone to breakage or damage, therefore limiting the effectiveness of their application. So far, no report on the compressive strength standard data of macroporous bioactive glass scaffolds has been found in previous patent and published documents and as a result, gives rise to the purpose of this invention to determine proper technical control measures to keep the compressive strength of the manufactured bioactive glass scaffold within a certain range to meet the requirements of various applications.